The Experimental Pathology core will provide the necessary infrastructure, technical and professional support to perform pathologic and molecular analyses of mouse and human pancreatic ductal neoplasms.. Detailed histopathologic examinations of genetically engineered mice (GEM) will be performed to identify tumors, characterize whether they display pancreatic ductal differentiation and identify the presence of metastases. The following models will be analyzed: GEM with Kras activation and combinations of p53, Ink4a/Arf and/or Smad4 inactivation (Project 1);GEM targeting PI3 kinase pathway components (Project 2); GEM (from Project 1 and 2) entered into preclinical chemotherapeutic trials (Project 3);and GEM constructed to assess early lesions and cell of origin (Project 4). A central goal is to understand the morphologic progression of mouse pancreatic neoplasms. Duct epithelial lesions, including the size, extent, grade and multifocality of pancreatic intraepithelial neoplasms (PanlNs) will be assessed in each model and correlated with genotype to delineate the biologic role of specific genetic lesions in morphologic progression. Correlations will be made with findings from the Imaging Core to refine the results of novel diagnostic strategies. The Core will also support the immunohistochemical analysis of mouse neoplasms including signature pancreatic pathways (Project 1), PI3 kinase signaling (Project 2), tumor microenvironment (Project 3) and tumor stem cell compartments (Project 4). Novel monoclonal antibodies for use in immunohistochemical assays will be developed in conjunction with the Antibody Core. Putative amplicon genes for new models will be screened in human samples by FISH. The validity of these models will be examined by characterizing these same pathways and cell compartments in human pancreatic ductal adenocarcinomas and PanlNs. Provisions of human tissue samples and their analysis will be performed in collaboration with the BioBank Core, and will test the hypothesis that GEM models may yield important insights into human pancreatic carcinogenesis. These investigations of mice engineered to develop pancreatic tumors will define the genetic basis of mouse tumor development, providing advances in understanding of human pancreatic cancer, and leading to systems for the testing of new therapies specifically targeting biologic pathways.